The present invention relates to a method for producing optically active xcex1-aminonitriles and xcex1-amino acids. More specifically, the invention relates to a novel method, which enables the synthesis of optically active xcex1-aminonitriles followed by the synthesis of optically active xcex1-amino acids in high yield and high stereoselectivity.
Various xcex1-amino acids and xcex1-aminonitriles, as intermediates thereof, are useful substances in various fields such an pharmaceuticals, agricultural chemicals, toiletries and other such chemical products, an well an in the fold of functional polymers.
With respect to the synthesis of these useful substances, lately, there have been some reports on the method of catalytic asymmetric synthesis of xcex1-aminonitriles.
However, since such formerly reported methods of asymmetric synthesis use isolated and purified imines, in most cases, problems such as the limit in their application to imines derived from unstable aliphatic aldehydes, and low asymmetric yield exist.
Therefore, in the present invention, the object is to provide a solution to the above-mentioned problems of the conventional asymmetric synthesis, and to provide a novel method which enables the synthesis of optically active xcex1-aminonitriles, and further, the synthesis of optically active xcex1-amino acids, in high asymmetric yield, without going through imines, even when using unstable aldehydes as starting materials.
The present invention firstly provides, as a means to solve the above-mentioned problems, a method for producing optically active xcex1-aminonitriles, which comprises reacting an aldehyde compound, an amino compound and hydrogen cyanate in the presence of a chiral zirconium catalyst obtained by mixing a zirconium alkoxide with at least one optically active binaphthol compound.
Also, the present invention secondly provides a method for producing optically active xcex1-aminonitriles, wherein the optically active binaphthol compound is at least one compound selected from 3,3xe2x80x2-dibromo-1,1xe2x80x2-bi-2-naphthol and 6,6xe2x80x2-dibromo-1,1xe2x80x2-bi-2-naphthol. The invention thirdly provides a method for producing optically active xcex1-aminonitrile, wherein the reaction in conducted in the presence of an imidazole compound.
Further, the present invention fourthly provide the method for producing optically active xcex1-aminonitriles according to any one of the first to third inventions, wherein an aldehyde compound represented by the formula
R1CHO
(wherein R1 represents a hydrocarbon group which may include one or more substituents) in reacted with an amino compound represented by the formula 
(wherein R2 represents a hydrogen atom or a hydrocarbon group which may include a substituent) and hydrogen cyanate to produce an optically active xcex1-aminonitrile represented by the formula 
(wherein R1 and R2 are as described above).
Furthermore, the present invention fifthly provides a method for producing an optically active xcex1-amino acid, which comprises converting the cyano group of the optically active xcex1-aminonitrile produced by any one of the methods of the first to fourth inventions to a carboxyl group or its derivative.
Also, the invention provides, sixthly, a method for producing an optically active xcex1-amino acid ester, which comprises converting the cyano group of the xcex1-aminonitrile obtained by the method of the fourth invention to an ester group, followed by its oxidative decomposition to form an optically active xcex1-amino acid ester represented by the formula 
(wherein R and R1 are hydrocarbon groups which may include one or more substituents).
Seventhly, the present invention provides a method for producing a pipecolic acid outer represented by the formula 
(wherein R is as described above) which comprises the deprotection and protection of the phenolic hydroxyl group of the xcex1-aminonitrile of the following formula 
(wherein R3 represents a protecting group), obtained by the process of the fourth invention to form the compound represented by the formula 
(wherein R4 represents a protecting group), followed by cyclization and esterification to form the ester compound represented by the formula 
(wherein R4 is an described above, and R represents a hydrocarbon group which my contain one or more substituent), which is then oxidatively decomposed.
The invention described above enables new development in the long-known Strecker synthesis. That is, although the Strecker synthesis is a method for producing synthetic amino acids wherein xcex1-aminonitriles are synthesized by the main-component condensation of ammonia, aldehyde and hydrogen cyanate, development of this method as a method of asymmetric synthesis has been an unexplored task. Under the situation, the inventors of the prevent invention have so far proposed the asymmetric Strecker-type reaction using trialkyltin cyanide as the cyano source (Japanese Patent Provisional Publication No. 255,730/1999). In the present invention, the formation of xcex1-aminonitriles by asymmetric synthesis using hydrogen cyanate as a cyano source is enabled.
In other words, the method for producing the optically active xcex1-aminonitrile of the present invention enables the realization of the asymmetric synthesis of xcex1-aminonitriles in high yield, directly from aldehyde compounds, amino compounds and hydrogen cyanate without going through an imine as in formerly known methods.
Further, the present invention also enables the production of optically active xcex1-amino acid in high yield.
The best mode for carrying out the invention described above in as described bellow.
Basically, in the invention,
(I) an aldehyde compound,
(II) an amino compound, and
(III) hydrogen cyanate (HCN),
are used as the starting materials, reacted in the liquid phase in the presence of
(IV) a chiral zirconium catalyst to asymmetrically synthesize xcex1-aminonitrile.
The starting materials, the aldehyde compound (I) and the amino compound (II), maybe aldehydes and amines of various structures, such an aliphatic, alicyclic, aromatic, araliphatic or heterocyclic aldehydes and amines. The method of the present invention is applicable to unstable substances such as aliphatic aldehydes which were deemed to be unusable in formerly known asymmetric synthesis of xcex1-aminonitriles, which were performed via imines.
In the aldehyde compound (I), an aldehyde group (xe2x80x94CHO) may be bound to primary, secondary or tertiary carbon atoms, CH2xe2x80x94, CHxe2x80x94 or Cxe2x80x94. Further, the amino compound (II) may be a primary amine or a secondary amine with amino groups such as NH2 and NH. It is preferable to use a primary amine (xe2x80x94NH2) compound as the amino compound (II).
The chiral zirconium catalyst (IV) used in the present invention is obtained by mixing a zirconium alkoxide of the following formula
Zr(OR)4
(wherein R in a hydrocarbon group which may contain one or more substituents), with an optically active binaphthol compound. The hydrocarbon group constituting the alkoxy group (xe2x80x94OR) of the zirconium alkoxide may be aliphatic, alicyclic aromatic or other hydrocarbon groups, but is preferably an aliphatic hydrocarbon group such as an alkyl group. Appropriate examples of such alkyl group include lower alkyl groups such as a methyl group, an ethyl group, an n-propyl group (nPr), an isopropyl group (iPr), an n-butyl group (nBu), an isobutyl group (iBu), a tert-butyl group (tBu), an n-pentyl group (nPent), an isopentyl group (iPent) and an n-hexyl group (nHex).
The four alkoxide group (xe2x80x94OR) constituting the zirconium alkoxide (Zr(OR)4) may all be the same or different.
The optically active binaphthol compound to be mixed with the zirconium alkoxide may contain appropriate substituents in the naphthalene ring, and more than one optically active binaphthol compounds may be used in the mixing. Examples of the substituent are a halogen atoms such as chlorine, bromine or fluorine, alkyl groups, alkoxy groups, halo-substituted alkyl groups and alkoxy-substituted alkyl groups. Binaphthol compounds having the same substituents in a symmetric position on the two naphthalene rings is more preferable. Specific examples thereof include optically active 3,3xe2x80x2-dibromo-1,1xe2x80x2-bi-2-naphthol and optically active 6,6xe2x80x2-dibromo-1,1xe2x80x2-bi-2-naphthol.
In the reaction, the zirconium alkoxide and the binaphthol compound may be added to the reaction system in a premixed state or may be mixed in the reaction system.
Also, in such asymmetric synthesis, which uses chiral zirconium catalyst (IV) of the present invention, a nitrogen-containing compound, preferably, a nitrogen-containing compound forming a tertiary amino group, such as an N-alkyl-substituted imidazole compound, may be present in the reaction system. The presence of such nitrogen-containing compound may improve the reactivity.
In the method of asymmetric synthesis of xcex1-aminonitriles of the present invention, an appropriate reaction solvent may be used. Examples of such solvent include halogenated hydrocarbons, acetonitrile, DMF and DMSO.
The amount of the starting materials and the catalyst used in the asymmetric synthesis are not particularly limited; however, for the starting materials, the molar ratio, aldehyde compound (I)/amino compound (II)/HCN(III), may generally be controlled to 1/0.1 to 10/0.1 to 10. Further, for the chiral zirconium catalyst (IV), the amount of the zirconium alkoxide is preferably 1 to 20 mol %, the amount of the binaphthol 1 to 50 mol %, and the amount of the nitrogen-containing compound 40 mol % or less.
In the method for asymmetric synthesis of xcex1-aminonitrile of the present invention, the reaction temperature is preferably xe2x88x9270xc2x0 C. to 30xc2x0 C. Further, the reaction pressure may be reduced bellow atmospheric pressure or in the rage of atmospheric pressure to 2 atm.
Considering the toxicity of hydrogen cyanate, the reaction is preferably conducted under low temperature, in the presence of a solvent that excels in absorption solubility of hydrogen cyanate, or pressurize by an inert gas such as argon or nitrogen. The starting material, hydrogen cyanate (HCN), may be supplied as a gas or may be generated in the liquid phase of the reaction system.
From the method of the present invention, for example, an optically active xcex1-(N-aryl-substituted amino) nitrile compound is obtained in high yield by the reaction of an aldehyde compound (R1CHO) with a 2-hydroxy-6-R2-substituted-aniline and HCN, as stated above.
Such xcex1-aminonitrile enables the selective formation of optically active xcex1-amino acids, through the decomposition of the cyano group or the convertion to a carboxyl group or its derivative such as an ester group through esterification.
Some of the optically active xcex1-amino acids are important because they possess bioactivity or biological activity. Further, selective synthesis of pipecolic acid may also he realized through the prevent invention, as stated earlier.